Cloning and sequencing of human betaIII-tubulin cDNA: induction of betaIII isotype in human prostate carcinoma cells by acute exposure to antimicrotubule agents.
Antimicrotubule drugs are used as chemotherapeutic agents due to their effects on essential cellular functions such as mitosis, organelle transport and maintenance of cell shape. When used in combination, paclitaxel with estramustine or vinblastine has demonstrated activity against hormone refractory prostate cancer. To understand the mechanism of resistance that develops in patients as a result of antimicrotubule drug therapy, we exposed human prostate carcinoma cells to IC20 and IC40 doses of estramustine, paclitaxel or vinblastine for 48 h and examined the beta-tubulin (the cellular target) isotype composition. The results revealed an increase in the betaIII-tubulin isotype as a result of drug treatment both at protein and message levels. In addition, examination of human brain cell lines with different intrinsic levels of betaIII showed that cell lines with higher betaIII levels were more resistant to paclitaxel. These results are in agreement with our previous findings in human prostate carcinoma cell lines that were made resistant to estramustine or paclitaxel and suggest an important function for betaIII in antimicrotubule drug resistance. Also, the complete coding sequence of human betaIII tubulin reported here will provide molecular tools for future investigations.
Ranganathan
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S
Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Dexter
D W
DW
Benetatos
C A
CA
Hudes
G R
GR
D000595:Amino Acid Sequence; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001483:Base Sequence; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004351:Drug Resistance; D004961:Estramustine / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008870:Microtubules; D008969:Molecular Sequence Data; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D014404:Tubulin / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology*
D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D018076:DNA, Complementary; D014404:Tubulin; D004961:Estramustine; D014747:Vinblastine; D017239:Paclitaxel